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Lymphoma: an introduction into historical background, classification schemes, aetiology, geographical variation and epidemiological trend

Peh SC, Poppema S

Malays J Pathol, 2001 Dec;23(2):49-63.
PMID: 12166593
Matched MeSH terms: Lymphoma/virology*
Epstein-Barr virus: more than 50 years old and still providing surprises

Young LS, Yap LF, Murray PG

Nat Rev Cancer, 2016 12;16(12):789-802.
PMID: 27687982 DOI: 10.1038/nrc.2016.92

It is more than 50 years since the Epstein-Barr virus (EBV), the first human tumour virus, was discovered. EBV has subsequently been found to be associated with a diverse range of tumours of both lymphoid and epithelial origin. Progress in the molecular analysis of EBV has revealed fundamental mechanisms of more general relevance to the oncogenic process. This Timeline article highlights key milestones in the 50-year history of EBV and discusses how this virus provides a paradigm for exploiting insights at the molecular level in the diagnosis, treatment and prevention of cancer.

Matched MeSH terms: Lymphoma/virology
Fulltext Herpes zoster in children with cancer

Menon BS, Wan Maziah WM

Malays J Pathol, 2001 Jun;23(1):47-8.
PMID: 16329548

The aim of this study was to determine the incidence and outcome of herpes zoster hospitalised children with cancer in Kota Baru. It was a retrospective review from January 1994 to December 1998. The diagnosis of herpes zoster was a clinical one. Herpes zoster was diagnosed in 10 of 188 (5%) children with malignancy. The most common malignancy was leukaemia. Nine children were treated with acyclovir. No child developed visceral dissemination and there were no deaths.

Matched MeSH terms: Burkitt Lymphoma/virology*; Precursor Cell Lymphoblastic Leukemia-Lymphoma/virology*
Epstein-Barr virus latent membrane protein-1 oncogene deletions: correlations with malignancy in Epstein-Barr virus--associated lymphoproliferative disorders and malignant lymphomas

Kingma DW, Weiss WB, Jaffe ES, Kumar S, Frekko K, Raffeld M

Blood, 1996 Jul 01;88(1):242-51.
PMID: 8704180

LMP-1, an Epstein-Barr viral (EBV) latency protein, is considered a viral oncogene because of its ability to transform rodent fibroblasts in vivo and render them tumorigenic in nude mice. In human B cells, EBV LMP-1 induces DNA synthesis and abrogates apoptosis. LMP-1 is expressed in EBV-transformed lymphoblastoid cell lines, nasopharyngeal carcinoma (NPC), a subset of Hodgkin's disease (HD), and in EBV-associated lymphoproliferative disorders (EBV-LPDs). Recently, focused deletions near the 3' end of the LMP-1 gene (del-LMP-1, amino acids 346-355), in a region functionally related to the half-life to the LMP-1 protein, have been reported frequently in human immunodeficiency virus (HIV)-associated HD (100%) and EBV+ Malaysian and Danish peripheral T-cell lymphomas (100%, 61% respectively), but less frequently in cases of HD not associated with HIV (28%, 33%) and infectious mononucleosis (33%). To further investigate the potential relationship of del-LMP-1 to EBV-LPDs associated with immunosuppression or immunodeficiency, we studied 39 EBV-associated lymphoproliferations (10 benign, 29 malignant) from four distinct clinical settings: posttransplant (4 malignant, 1 reactive); HIV+ (18 malignant, 2 reactive); nonimmunodeficiency malignant lymphoma (ML) (7 cases); and sporadic EBV infection with lymphoid hyperplasia (7 cases). The presence of EBV within lymphoid cells was confirmed by EBV EBER1 RNA in situ hybridization or by polymerase chain reaction (PCR) analysis. EBV strain type and LMP-1 deletion status were determined by PCR. EBV strain types segregated into two distinct distributions: HIV+ (9 A; 11 B) and non-HIV (19 A, 0 B), consistent with previous reports. Overall, del-LMP-1 were found in 1 of 5 (20%) Burkitt lymphomas (BL); 17 of 24 (71%) aggressive non-Hodgkin's lymphoma (agg-NHL), and 2 of 10 (20%) reactive lymphoid proliferations. Of the agg-NHLs, del-LMP-1 were present in 4 of 4 PT-ML (100%); 10 of 15 HIV+ ML (67%); and 3 of 5 nonimmunodeficiency malignant lymphoma (ML, 60%). A total of 2 of 7 (28%) sporadic EBV-associated lymphoid hyperplasias contained a del-LMP-1. All del-LMP-1 were identical by DNA sequence analysis. No correlation was identified between the presence of del-LMP-1 and the EBV strain type observed. The high incidence of del-LMP-1 observed in agg-NHLs (71%), in contrast to the relatively low incidence observed in reactive lymphoid proliferations (28%), suggests that the deleted form may be preferentially selected in lymphomatous processes. All posttransplant agg-NHLs contained a del-LMP-1, and a similar frequency of del-LMP-1 was observed in both HIV-associated ML (66%) and nonimmunodeficiency ML (60%), suggesting that impairment of immune function alone is not a requirement for the expansion of malignant cells infected by EBV stains containing the deleted LMP-1 gene.

Matched MeSH terms: Burkitt Lymphoma/virology; Lymphoma/virology*
Fulltext Inhibitory activities of microalgal extracts against Epstein-Barr virus DNA release from lymphoblastoid cells

Kok YY, Chu WL, Phang SM, Mohamed SM, Naidu R, Lai PJ, et al.

J Zhejiang Univ Sci B, 2011 May;12(5):335-45.
PMID: 21528487 DOI: 10.1631/jzus.B1000336

This study aimed to assess the inhibitory activities of methanol extracts from the microalgae Ankistrodesmus convolutus, Synechococcus elongatus, and Spirulina platensis against Epstein-Barr virus (EBV) in three Burkitt's lymphoma (BL) cell lines, namely Akata, B95-8, and P3HR-1. The antiviral activity was assessed by quantifying the cell-free EBV DNA using real-time polymerase chain reaction (PCR) technique. The methanol extracts from Ankistrodesmus convolutus and Synechococcus elongatus displayed low cytotoxicity and potent effect in reducing cell-free EBV DNA (EC(50)<0.01 µg/ml) with a high therapeutic index (>28000). After fractionation by column chromatography, the fraction from Synechococcus elongatus (SEF1) reduced the cell-free EBV DNA most effectively (EC(50)=2.9 µg/ml, therapeutic index>69). Upon further fractionation by high performance liquid chromatography (HPLC), the sub-fraction SEF1'a was most active in reducing the cell-free EBV DNA (EC(50)=1.38 µg/ml, therapeutic index>14.5). This study suggests that microalgae could be a potential source of antiviral compounds that can be used against EBV.

Matched MeSH terms: Burkitt Lymphoma/virology
High frequency of EBV association and 30-bp deletion in the LMP-1 gene in CD56 lymphomas of the upper aerodigestive tract

Tai YC, Kim LH, Peh SC

Pathol. Int., 2004 Mar;54(3):158-66.
PMID: 14989738

Natural killer (NK)/T-cell lymphomas are frequently associated with Epstein-Barr virus (EBV), and usually lack TCR gene rearrangement. Studies from Asia have reported frequent deletion in the LMP-1 gene in EBV-associated nasopharyngeal carcinoma (NPC). The present study aims to investigate LMP-1 and TCRgamma gene status in upper aerodigestive tract lymphomas. A total of 43 cases were classified into T-, B-, and NK/T-cell tumors based on the phenotype expressions of CD3(+)/CD20(-)/CD56(-), CD3(-)/CD20(+)/CD56(-), and CD3(+)/CD20(-)/CD56(+), respectively. The presence of EBV in the tumor was confirmed by EBV early RNA-in situ hybridization. LMP-1 gene deletion and TCR gamma gene rearrangement were analyzed by polymerase chain reaction on paraffin-embedded tissues. There were 20 NK/T-, eight T-, and 15 B-cell phenotype lymphomas in the present series, and EBV was detected in 19 (95%), two (25%), and three (20%) cases in the respective groups. All EBV+ cases carried 30-bp deletion in the LMP-1 gene, and two of the NK/T-cell cases were infected by both the wild type and deleted strains. Five (25%) of the NK/T-cell phenotype lymphomas showed rearranged TCR gamma gene. The present study revealed a high frequency of EBV association, and a high frequency of 30-bp deletion in the LMP-1 gene in the virus in the present series of lymphoma. The NK/T-phenotype lymphomas are comprised of both NK-cell and cytotoxic T-lymphocyte-derived tumors.

Matched MeSH terms: Lymphoma/virology*
Fulltext Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma

Higuchi H, Yamakawa N, Imadome KI, Yahata T, Kotaki R, Ogata J, et al.

Blood, 2018 06 07;131(23):2552-2567.
PMID: 29685921 DOI: 10.1182/blood-2017-07-794529

Epstein-Barr virus (EBV) causes various diseases in the elderly, including B-cell lymphoma such as Hodgkin's lymphoma and diffuse large B-cell lymphoma. Here, we show that EBV acts in trans on noninfected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between 2 EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata-derived exosomes affected LPD severity, possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata-lymphoblastoid cell lines reportedly contain EBV-derived noncoding RNAs such as BamHI fragment A rightward transcript (BART) micro-RNAs (miRNAs) and EBV-encoded RNA. We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of interleukin 10, tumor necrosis factor-α, and arginase 1, suggesting the immune regulatory role of BART miRNAs. The expression level of an EBV-encoded miRNA was strongly linked to the clinical outcomes in elderly patients with diffuse large B-cell lymphoma. These results implicate BART miRNAs as 1 of the factors regulating the severity of lymphoproliferative disease and as a diagnostic marker for EBV+ B-cell lymphoma.

Matched MeSH terms: Lymphoma/virology*
Frequent presence of subtype A virus in Epstein-Barr virus-associated malignancies

Peh SC, Kim LH, Poppema S

Pathology, 2002 Oct;34(5):446-50.
PMID: 12408344

AIMS: Epstein-Barr virus (EBV) is associated with many human malignancies. It is implicated in a pathogenetic role in some of these tumours. Two subtypes, type A and B have been identified on the basis of DNA sequence divergence in the nuclear protein genes (EBNA) 2, 3, 4 and 6. They differ in their transforming efficiency and prevalence pattern in different geographical locations. We aimed to identify the virus subtype infection pattern in our EBV-associated diseases.
METHODS: Paraffin-embedded tissue from 38 lymphomas (17 Hodgkin's, 14 Burkitt's, four T cell and 3 B cell non-Hodgkin's lymphomas) and 14 nasopharyngeal carcinomas (NPC) were studied, with 12 reactive lymph nodes and tonsils as normal control. EBER in situ hybridisation was performed to confirm EBV association in the tumour cells. A nested polymerase chain reaction (PCR) protocol was employed using two pairs of consensus primers which flanked a 105-bp deletion in the type A virus. U2 region encoding for EBNA-2 was chosen as the target of amplification, with cell lines B95.8 and AG876 serving as positive controls for types A and B virus, respectively.
RESULTS: All cases showed presence of type A virus, consistently detected with nested PCR protocol but not with single step PCR. There was no type B virus or mix infections detected.
CONCLUSIONS: Nested PCR technique has successfully increased the sensitivity of EBV subtype detection, and type A virus is the prevalent strain associated with human diseases in Malaysia.

Matched MeSH terms: Lymphoma/virology*
Differential attenuation of Marek's disease virus-induced tumours and late-Marek's disease virus-induced immunosuppression

Faiz NM, Cortes AL, Guy JS, Reddy SM, Gimeno IM

J Gen Virol, 2018 07;99(7):927-936.
PMID: 29767614 DOI: 10.1099/jgv.0.001076

Marek's disease virus (MDV) is a herpesvirus that induces lymphoma and a variety of non-neoplastic syndromes in chickens. Furthermore, very virulent plus (vv+) MDVs induce a form of immunosuppression (late-MDV-IS) that might involve both neoplastic and non-neoplastic mechanisms. The objective of this study was to evaluate whether the attenuation of MDV-induced tumours and late-MDV-IS occurs simultaneously or can be dissociated. The immunosuppressive ability of three viruses derived from vv+ MDV strain 686 (wild-type 686, the somewhat attenuated molecular clone 686-BAC, and the nononcogenic molecular clone lacking the two copies of the oncogene meq 686-BACΔMEQ) was evaluated. Late-MDV-IS was evaluated indirectly by assessing the negative effect of MDV strains on the protection conferred by infectious laryngotracheitis (ILT) vaccines. Our results showed that the ability to induce late-MDV-IS was attenuated before the ability to induce tumours. Strain 686 induced both tumours and late-MDV-IS, 686-BAC induced tumours but did not induce late-MDV-IS and 686-BACΔMEQ did not induce either tumours or late-MDV-IS. Further comparison of strains 686 and 686-BAC revealed that strain 686 reduced the humoral immune responses to ILTV (1132 vs 2167) more severely, showed higher levels of meq transcripts (2.1E+09 vs 4.98E+8) and higher expression of MDV microRNAs (mdv1-miR-M4-5p and mdv1-miR-M2-3p) in the spleen, and further reduced the percentage of CD45+-MHC-I+splenocytes (13 vs32 %) compared to molecular clone 686-BAC. This study suggests that the immunosuppressive ability of MDV might follow a continuous spectrum and only the most virulent MDVs can overcome a certain threshold level and induce clinical MDV-IS in the ILT model.

Matched MeSH terms: Lymphoma/virology